ZFIN ID: ZDB-PUB-181020-18
SREBP-1 and LXRα pathways mediated Cu-induced hepatic lipid metabolism in zebrafish Danio rerio
Pan, Y.X., Zhuo, M.Q., Li, D.D., Xu, Y.H., Wu, K., Luo, Z.
Date: 2018
Source: Chemosphere   215: 370-379 (Journal)
Registered Authors:
Keywords: Copper, Danio rerio, LXRα, Lipid metabolism, SREBP1, Transcriptomic analysis
MeSH Terms:
  • Animals
  • Copper/pharmacology*
  • Hepatocytes/metabolism
  • Lipid Metabolism/drug effects*
  • Lipids
  • Liver/metabolism*
  • Liver X Receptors/metabolism*
  • Sterol Regulatory Element Binding Protein 1/metabolism*
  • Water Pollutants, Chemical/metabolism
  • Zebrafish/metabolism
PubMed: 30336314 Full text @ Chemosphere
The present study was performed to explore the underlying molecular mechanism of Cu-induced disorder of lipid metabolism in fish. To this end, adult zebrafish were exposed to three waterborne Cu concentrations (0 (control), 8 and 16 μg Cu/L, respectively) for 60 days. Hepatic Cu content and hepatosomatic index increased after waterborne Cu exposure. H&E and oil red O stainings showed extensive steatosis in the liver of Cu-exposed fish. Cu exposure up-regulated lipogenic enzymes activities of ME, ICDH, 6PGD, G6PD and FAS, but down-regulated CPTI activities. Transcriptomic analysis indicated that lipid metabolism related pathways were significantly enriched in both low-dose and high-dose Cu exposure group. Genes involved in lipogenic process from fatty acid biosynthesis, fatty acid elongation, fatty acid desaturation to glycerolipid biosynthesis were up-regulated by Cu. To elucidate the mechanism, LXRα inhibitor SR9243 and SREBP1 inhibitor fatostatin were used to verify the role of LXRα and SREBP1 in Cu-induced disorder of lipid metabolism. Both SR9243 and fatostatin significantly attenuated the Cu-induced increase of TG accumulation of hepatocytes. Meanwhile, SR9243 significantly attenuated the Cu-induced up-regulation of expression of lipogenic genes (acaca, fas, icdh, dgat1, moat2 and moat3), and fatostatin significantly attenuated the up-regulation of expression of acaca, fas, g6pd, dgat1 and moat2. Enzymes analysis showed both SR9243 and fatostatin blocked the Cu-induced increase of lipogenic enzymes activities. Taken together, our findings highlight the importance of LXRα and SREBP1 in Cu-induced hepatic lipid deposition, which proposed a novel mechanism for elucidating metal element exposure inducing the disorder of lipid metabolism in aquatic vertebrates.